I describe a systems approach to develop and implement novel methods to explore model receptor-mediated signaling in extrinsic apoptosis in mammalian cells based on experimental data. My focus will be on the signaling events from ligand binding at the cellular surface to mitochondrial outer membrane permeabilization and eventual effector caspase activation. The discoveries from this work will also have an impact in prototypical cue-signal-response pathways in molecular cancer cell biology and related fields. I will examine the validity of different competing mechanisms for mitochondrial outer membrane permeabilization using theoretical approaches and complement this with experimental data collected in our laboratory. The calibration of such a model to experimental data will be central aspect of my work. I expect the development of novel theories about apoptosis which will suggest new research directions. A second stage of the proposed work will expand the models to examine the effect of drugs on transformed and non-transformed cells of different types, also based on experimental data. Concurrent with the biological work, I will develop tools that will allow for flexible treatment of complex network models thus facilitating the biological studies. Attention to model tracking, model sharing, and its connection with experiments will be given special attention through the use of semantic- Wiki based software developed in our laboratory for dissemination and outreach of the project. Toward the independent part of the award I will merge my newly acquired cancer molecular cell biology knowledge with my theoretical physical chemistry training to develop tools which accurately describe cellular environments and implement methods to reduce the number of parameters that are difficult to obtain in current modeling efforts. I expect my project to have a profound impact on the study of signaling pathways in apoptosis, the understanding of drugs and their interactions with proteins related to apoptosis, and the development of tools rooted in the needs of cell molecular cancer biology. PUBLIC HEALTH RELEVANCE: Our study will provide new insights into the regulation and control of the extrinsic apoptosis pathway and its relation to cancer. These studies aim to unify the existing controversy as to the activation of apoptosis and commitment to the mitochondrial outer membrane permeabilization. In addition, novel analytic, modeling, and data annotation tools will be developed that will have deep impact on cancer treatment.